Date of Award

Summer 2004

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Electrical & Computer Engineering

Committee Director

Ravindra P. Joshi

Committee Member

Stephen J. Beebe

Committee Member

Linda L. Vahala

Committee Member

Karl H. Schoenbach

Committee Member

Stephen A. Zahorian

Abstract

The dynamics of electroporation of biological cells subjected to nanosecond, high intensity pulses are studied based on a coupled scheme involving the current continuity and Smoluchowski equations. The improved pore formation energy model includes a dependence on pore population and density. It also allows for variable surface tension and incorporates the effects of finite conductivity on the electrostatic correction term, which was not considered by the simple energy models in the literature. It is shown that E(r) becomes self-adjusting with variations in its magnitude and profile. The whole scheme is self-consistent and dynamic.

An electromechanical analysis based on thin-shell theory is presented to analyze cell shape changes in response to external electric fields. The calculations demonstrate that at large fields, the spherical cell geometry can be modified, and even ellipsoidal forms may not be appropriate to account for the resulting shape. It is shown that, in keeping with reports in the literature, the final shape depends on membrane thickness. This has direct implications for tissues in which significant molecular restructuring can occur.

This study is also focused on obtaining qualitative predictions of pulse width dependence to apoptotic cell irreversibility that has been observed experimentally. The analysis couples a distributed electrical model for current flow with the Smoluchowski equation to provide self-consistent, time-dependent transmembrane voltages. The model captures the essence of the experimentally observed pulse-width dependence, and provides a possible physical picture that depends only on the electrical trigger. Different cell responses of normal and malignant (Farage) tonsillar B-cell are also compared and discussed. It is shown that subjecting a cell to an ultrashort, high-intensity electric pulse is the optimum way for reversible intracellular manipulation.

Finally, a simple but physical atomistic model is presented for molecular motion within biological membranes subjected to electric fields. The dynamical, stochastic aspects are treated at the molecular level, without including each and every atom of the complex molecular system. The membrane lipid molecules are represented by a ball-spring model, with pair-wise Lennard-Jones interacting potentials. Predictions include pore formation times of around 1 ns, relatively low ionic throughput in keeping with recent observations, and currents of about 5 nA (at 500 kV/cm). It is also shown that ions facilitate pore formation and that membrane poration may be the principle route for phosphatidylserine externalization.

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DOI

10.25777/8sz8-nq26

ISBN

9780496076055

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